Our central hypothesis is that involutional osteoporosis in women is heterogeneous and results from impaired production of, or response to, several systemic and local regulatory factors. We have four specific aims covered by 12 interrelated protocols. Specific Aim 1: to characterize the short-term patterns of bone turnover (by measuring biochemical markers) in normal and osteoporotic women and the regulatory factors responsible for these patterns. We will assess day/night patterns of bone turnover, determine if the nocturnal decrease in bone formation depends on growth hormone, determine if the apparent nocturnal increase in bone resorption in osteoporotic women depends on parathyroid hormone (PTH) or prostaglandins, and search for evidence of functionally different osteoblast populations. Specific Aim 2: to elucidate the pathophysiology of type I osteoporosis more completely by searching for the interaction of estrogen deficiency with other factors that predispose some, but not other, postmenopausal women to osteoporosis. Possible factors include increased sensitivity of the bone to PTH actin, decreased concentration of sex steroid receptors, and impaired production of, or response to, local growth factors. specific Aim 3: to evaluate the contribution of resistance to 1,25-dihydroxyvitamin D (1,25(OH2D) action to abnormal calcium (Ca) homeostasis in elderly women. Our preliminary data suggest tat this, rather than decreased 1,250(OH)2D treatment, in concentrations of 1,25(OH)2D receptors or postreceptor responses, and in feedback regulation of PTH secretion by 1,25(OH)2D. Specific Aim 4: to define other pathogenetic mechanisms for the development of age-related bone loss and type II osteoporosis. We will evaluate age-related changes in the actions of estrogen and PTH on bone, in systemic hormone concentrations, in estrogen receptor concentrations in cultured human bone cells and in the response of these cells to growth factors. We have available virtually all methodologies for clinical investigation of osteoporosis including several new state- of-the-art ones. These studies should lead to a better understanding of etiology and pathophysiology of involutional osteoporosis and, ultimately, to better ways of preventing and treating it.